The basic theme of the Project is to relate systematic clinical data in Alzheimer's Disease with morphometry and biochemical exploration of postmortem tissue. In vivo tests on 300 demented patients and 100 matched control subjects include systematized neurological and psychiatric documentation, psychometric evaluation, EEG recordings and CT scanning. Some cases will also undergo extra cognitive and language studies, pattern VER recordings, and NMR imaging. The accuracy of antemortem diagnosis is being measured by autopsy findings from 75% of deceased cases. Ultimately the clinical data will be correlated with tissue study information from 55 paitents proven to have had pure Alzheimer's Disease postmortem. The latter data include quantification of the major neuropathological lesions in limbic, neocortical, and basal forebrain regions (tangles, plaques, granulovacuolar degeneration, Hirano bodies, neuron loss); assays of neurotransmitter markers, both pre- and post-synaptic (ChAT, AChE, MAO, QNB); and kinetics of choline transport and acetylcholine synthesis in synaptosomal preparations. Statistical analyses will be performed on all data. Eight clinical and five pathological Objectives define the scope of the Project in more detail. Four of these thirteen Objectives are new to this Competing Continuation application: (a) to determine the special character of those few patients found at autopsy to have SDAT, whose EEGs were repeatedly normal; (b) to decide whether the profile analysis or other discriminant function based on psychological tests will differentiate SDAT from other organic dementias; (c) to evaluate memory and language impairments more specifically in patients with early SDAT, and the contributions of these changes to differential diagnosis; and (d) to test the hypothesis that the frequency and/or severity of the histological and the biochemical lesions in the human basal forebrain can account for the degree of clinical impairment, and that these lesions underlie the pathogenetic mechanism of the cholinergic depletion. The fundamental prupose is to establish optimum techniques for diagnosing SDAT (senile demential Alzheimer type), and to detemrine which of the structural and biochemical lesions best accounts for the occurrence and extent of the clinical condition, in this most common cause of cognitive dysfunction in our elderly population.